International Journal of Pharmaceutics 395 (2010) 266–271 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Pharmaceutical Nanotechnology Intranasal delivery of zidovudine by PLA and PLA–PEG blend nanoparticles Rubiana Mara Mainardes a,∗ , Najeh Maissar Khalil a , Maria Palmira Daflon Gremião b a Universidade Estadual do Centro-Oeste/UNICENTRO, Departamento de Farmácia, Rua Simeão Camargo Varela de Sá 03, Guarapuava, PR 85040-080, Brazil b Universidade Estadual Paulista Júlio de Mesquita Filho/UNESP, Faculdade de Ciências Farmacêuticas, Departamento de Fármacos e Medicamentos, Rod. Araraquara-Jaú Km 01, Araraquara, SP 14801-902, Brazil article info Article history: Received 14 December 2009 Received in revised form 2 May 2010 Accepted 15 May 2010 Available online 24 May 2010 Keywords: Nanoparticles Intranasal administration Zidovudine Bioavailability abstract This study describes the preparation and evaluation of biodegradable poly(l-lactide) (PLA) and poly(l- lactide)–poly(ethylene glycol) (PLA–PEG) blend nanoparticles containing zidovudine as model drug. The prepared nanoparticles were characterized in terms of size, zeta potential, morphology and drug entrap- ment efficiency. The pharmacokinetics of zidovudine following intranasal administration in mice was assessed. The results showed that although PLA and blend nanoparticles had the same morphology, the particle size and zeta potential were changed by the PEG. The drug entrapment efficiency was increased by PEG presence. The pharmacokinetic study showed that all the nanoparticles were able to sustain zidovu- dine delivery over time, but greater efficiency was obtained with PLA–PEG blend nanoparticles, whose T max was twice that of PLA nanoparticles. The PLA and PLA–PEG nanoparticles formulations increased the zidovudine mean half-life by approximately 5.5 and 7 h, respectively, compared to zidovudine aqueous solution. The relative bioavailability of zidovudine-loaded PLA–PEG blend nanoparticles was 2.7, relative to zidovudine-loaded PLA nanoparticles and 1.3 relative to aqueous solution formulation. Thus, the PLA nanoparticles were unable to increase the zidovudine bioavailability compared to aqueous solution for- mulation. The results obtained in this study indicate the potential of the PLA–PEG blend nanoparticles as carriers for zidovudine delivery by the intranasal route. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Zidovudine (AZT) was the first antiretroviral agent developed and, upon approval in 1987, it became a key feature in the therapy of acquired immune deficiency syndrome (AIDS) (Chien and Wearley, 1989; Warnke et al., 2007). AZT is an analog of deoxythymidine and is activated to its mono-, di-, and triphosphates by cellular enzymes in both human immunodeficiency virus (HIV) infected and uninfected cells (Furman et al., 1986). The active metabolite, AZT triphosphate, inhibits HIV-1 reverse transcriptase as well as mitochondrial DNA polymerase-g (König et al., 1989). The major limitation in the use of AZT is the occurrence of severe side effects (Yarchoan et al., 1989). The most serious and frequent is the hematological toxicity, characterized by bone marrow sup- pression, which is usually manifested as anemia, neutropenia and thrombocytopenia (Gill et al., 1987; Kennedy et al., 1991). These toxic effects are dose-dependent. The adverse side effects of AZT may necessitate dose reduction or even cessation of therapy. The pharmacokinetics of AZT have been studied in humans and in animal species, showing that when it is administered orally, ∗ Corresponding author. Tel.: +55 42 36298137; fax: +55 42 36298102. E-mail addresses: rubianamainardes@pq.cnpq.br, rubianamainardes@hotmail.com (R.M. Mainardes). AZT is rapidly absorbed from the gastrointestinal tract, but is then rapidly metabolized to the inactive glucoronide with a mean elim- ination half-life (t 1/2 ) of 1 h, resulting in low oral bioavailability (∼60–65%) (Blum et al., 1988). An alternative route for AZT admin- istration could be an interesting way to increase it bioavailability. Also, a colloidal carrier used to entrap AZT could deliver it at a con- tinuous rate and reduce the dose-dependent toxicity by minimizing the fluctuations in plasma concentrations. Colloidal drug carriers are interesting in drug delivery sys- tems because their small size allows them to permeate through biological barriers (Nakada et al., 1996). The novel drug delivery systems for anti-HIV agents include micelles and microemulsions, liposomes, polymeric microparticles and nanoparticles (Ojewole et al., 2008). For nearly three decades, polymeric nanoparticles have been extensively studied because of their unique and valuable physicochemical and biological properties. Indeed, nanoparticles can protect the drug from degradation, enhance its transport and prolong its release; therefore, they may improve the plasma half- life of the drug (Oppenheim, 1981; Allémann et al., 1993). The pharmacokinetic parameters are altered with the nanoparticles and its surface composition plays an important role in drug bioavail- ability, that can be greater or lower than drug solution/powder depending on the polymer used (Ubrich et al., 2005; Hoffart et al., 2006). Since some nanoparticles’ characteristics, such as particle size and surface charge can be modulated by modifying some pro- 0378-5173/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2010.05.020